1. Field of the Invention
This invention resides in the field of alkylation reactions, cyclization reactions, and reactions involving substitutions at a nitrogen atom.
2. Description of the Prior Art
Cyclic polyamine chelators, which are cyclic amines whose nitrogen atoms have pendant arms attached thereto that are capable of coordinating metal cations, have a wide range of utility. Chelators of this type are disclosed by Lindoy, L. F., The Chemistry of Macrocyclic Ligand Complexes, University Press, Cambridge, 1989; and Bradshaw, J. S., et al., The Chemistry of Heterocyclic Compounds, John Wiley and Sons, New York, 1993, vol. 51. One use of these chelators is in the treatment of conditions caused by an excess of first transition series elements in the body. Iron overload anemias are examples of such conditions. See Rivkin, G., et al., Blood, vol. 90, no. 10, pp. 4180-4187 (Nov. 15, 1997). Another use is in altering the expression of enzymes containing first transition series metal cations as co-enzymes and by inhibiting replication of mammalian, parasitic, fungal, and bacterial cells and viruses. A disclosure of this use appears in Winchell, H. S., et al., U.S. Pat. No. 5,874,573, issued Feb. 23, 1999. A further use is in the formation of complexes with radioisotopic or paramagnetic metal cations. These complexes are useful in diagnostic radioisotopic and magnetic resonance imaging, and disclosures of how these complexes are used in this manner uses are found in Winchell, H. S., et al., U.S. Pat. Nos. 5,236,695, issued Aug. 17, 1993, 5,380,515, issued Jan. 10, 1995, 5,593,659, issued Jan. 14, 1997, and 5,409,689, issued Apr. 25, 1995.
Known methods for the synthesis of N-substituted cyclic polyamine begin with a laborious and costly multi-step synthesis of the unsubstituted cyclic polyamine. Additional steps are then performed to attach the chelating pendant arms to nitrogen atoms. These methods are disclosed by Parker, D., Aza Crowns in Macrocyclic Synthesis, Oxford Universtiy Press, Oxford, U. K., 1996, and by Wainwright, K. P., xe2x80x9cSynthetic and Structural Aspects of the Chemistry of Saturated Polyaza Macrocyclic Ligands Bearing Pendant Coordinating Groups Attached to Nitrogen,xe2x80x9d Coord. Chem. Rev. 1997, p. 166. As noted by Parker, the cyclization reactions when forming medium- and large-ring cyclic polyamines have an unfavorable entropy term to the overall free energy change. This makes it difficult to form cyclic polyaza compounds of medium and large ring sizes. To minimize this adverse thermodynamic effect and to inhibit the formation of undesired products, protective groups are typically added to the nitrogen groups of the linear starting materials. Another means of promoting the reaction is by template syntheses whereby the nitrogen groups that must be joined through a linkage to achieve the desired ring closure are placed in proximity to encourage them to react. A still further alternative is the use of reactive groups on the appropriate nitrogen atoms that are selective toward reaction with each other. In all of these reactions, polymerization competes with cyclization, and cyclization is typically the favored reaction only when the reactants are highly dilute.
The most common methods of forming the cyclic polyaza backbone are those that begin with a linear polyaza compound containing two primary amine groups and varying numbers of secondary amine groups, and proceed by adding one protective group to each of the nitrogen atoms of the linear compound, a typical protective group being p-toluene sulfonyl (xe2x80x9ctosylxe2x80x9d). The two amine groups that still contain a H atom (i.e., the amine groups that were originally primary amine groups) are then reacted with a bridging reagent containing two reactive groups capable of undergoing nucleophilic reactions. Examples of bridging groups that are used for this purpose are ditosylated diols, such as for example ditosylated ethylene glycol. The bridging reaction is performed under conditions that do not allow for quaternization of the protected secondary amine groups. The bridging reaction produces a cyclic polyamine backbone of the desired size in which one protective group (such as a tosyl group) is attached to each nitrogen atom in the cycle. Various side products are produced as well. The protected cyclic polyamine is purified and subjected to reactions to remove the protective groups. (When the protective groups are tosyl groups, for example, deprotection is achieved by heating the tosylated cyclic polyamines in strong acid at elevated temperatures.) The deprotected cyclic polyamine product is then purified from the reaction mixture, and additional reactions are performed to attach the desired pendant arms to the nitrogen groups, the pendant arms being groups that are capable of coordinating metal cations.
Template methods have been used in the preparation of a limited number of cyclic polyamines. One such polyamine is cyclam, and a description of its synthesis using a template method is offered by Barefield, E. K., et al., Inorg. Synth., vol. 16, p. 220 (1976). When metal cation (for example, nickel) is used as the template, the cation must be removed from the reaction mixture to obtain the free cyclic polyamine. The procedure for removing the metal cation often introduces contaminants that must themselves be removed before the cyclic polyamine can be reacted further in syntheses to generate the N-substituted cyclic polyamine chelator.
Cyclization can also be achieved by amide formation, since primary amines are typically favored over secondary amines in reactions between esters and amine groups to form amides. Thus, moderate yields of cyclic compounds containing two amide groups can be obtained in some cases by reacting a linear polyamine containing two primary amine groups with a bridging compound containing two ester groups. An example is the reaction between dipropylamine triamine with the diethyl ester of malonic acid, described by Helps, I. M., et al., J. Chem. Soc. Perkin Trans. I (1989), 2079. This reaction can be followed by reduction of the amide bonds to form the desired amines. As in methods described above, cyclization competes with polymerization, and to achieve selectivity toward cyclization the reactants in these amide formation reactions are typically used in dilute concentrations. Even with dilute reaction mixtures, the yields of the cyclic diamides are often modest, and reduction of the amide bonds and subsequent purification of the desired cyclic polyamine may prove difficult.
A further synthesis route is based on the tendency of xcex1-chloroacetamides to favor reaction with secondary amines. In high dilution, therefore, one can produce certain cyclic diamides by reacting bis-xcex1-chloroacetamides with certain secondary amines. A disclosure of this reaction is offered by Krakowiak, K. E., et al., Synlett. (1993), 611. The resulting diamide is then reduced to obtain the desired cyclic polyamine. This synthesis can only produce cyclic polyamines containing four or more nitrogen groups, and as in the above-described methods, requires highly dilute reactants to favor cyclization over polymerization.
Difficulties also exist in syntheses of N-monoalkylated amines that still contain H atoms attached to one or more of the N atoms, and in which the alkyl substitution on each N atom is a pendant arm capable of coordinating metal cations. Iveson, P. B., et al., xe2x80x9cMonitoring the Moedritzer-Irani Synthesis of Aminoalkyl Phosphonates,xe2x80x9d Polyhedron, vol. 12, no. 19, pp. 2313-23 (1993) demonstrate that primary amines once substituted are disubstituted at a much greater rate than the initial substitution, thereby favoring disubstitution of the primary amine rather than monosubstitution. This difficulty is evidenced by the fact that there are no published reports of direct synthesis of either N,Nxe2x80x2,Nxe2x80x3-tris(methylenephosphonic acid)-1,4,7-triazaheptane (in which each nitrogen is monosubstituted with a methylenephosphonate moiety) or its esterified products.
A novel process for the cyclization of polyamines has now been discovered that produces the cyclic product in high yield and at low cost, and is capable of doing so in concentrated solutions rather than dilute solutions. The polyamines that are addressed by this process are those in which all nitrogen atoms except two are fully substituted, the remaining two bearing only one H atom. Some or all of the nitrogen atoms are monosubstituted with pendant arms capable of coordinating metal cations, or with precursors that can be converted to such pendant arms by simple chemical reactions. The cyclization is performed by the use of a bridging agent containing two sites that each bear a reactive group capable of undergoing a nucleophilic attack by one of the N-H groups on the polyamines. When such nucleophilic attack is on an oxo group the intermediate formed is subsequently reduced to form the desired product. This invention also resides in a novel process for the introduction of no more than one methylenephosphonate ester groups as substituents on the nitrogen atoms of linear polyamines, by reacting the polyamines with a tri-substituted phosphite and a source of formaldehyde in the presence of water. The process results in the placement of one methylenephosphonate ester group on each primary and secondary nitrogen atom. The resulting methylenephosphonate ester-substituted linear polyamines can then be cyclized in accordance with the cyclization reaction described above, and hydrolysis of the some or all of the ester groups to acid groups can be performed either on the linear product or on the cyclic product. Still further, this invention resides in a novel class of N,Nxe2x80x2,Nxe2x80x3-tris(methylene-phosphonate or methylenephosphonic acid-substituted)-1,4,7-triazaheptanes.
In the aspects of this invention that relate to the cyclization of polyamines, the starting polyamine has the formula 
in which:
R1 and R5 are either the same or different and are substituents capable of coordinating metal cations, or precursors that are convertible to such substituents,
R2 and R4 either the same or different and are unsubstituted or substituted alkyl, aryl, alkylaryl, or alkylarylalkyl groups,
R3 is either:
(a) a pendant arm capable of coordinating a metal cation, a precursor convertible to such a pendant arm, or an unsubstituted or substituted alkyl, aryl, alkylaryl, or alkylarylalkyl group, or
(b) a divalent unsubstituted or substituted alkyl radical forming a cyclic group with either R2 or R4 and the N atom to which R3 is bonded, and
n is 0, 1, 2, 3, 4, 5, or 6.
When n is 2 or greater, the R3s may be the same or different, although still within the above definition of R3, and likewise the R4s may be the same or different, although still within the above definition of R4. For embodiments in which R3 falls within part (b) of its definition, the starting compound already bears a cyclic structure but still contains the two N-H groups available for the cyclization reaction of this invention.
The cyclic compound produced by the cyclization reaction of this invention has the formula 
in which R6 is an unsubstituted or substituted alkyl, aryl, alkylaryl, or alkylarylalkyl group.
Throughout this specification and claims, the term xe2x80x9calkylxe2x80x9d is used to denote any saturated hydrocarbyl group, branched, unbranched, or cyclic. Acyclic alkyl groups are preferred, and unbranched acyclic alkyl groups are particularly preferred. As the formulas indicate, alkyl groups in the definitions of R2, R4, and R6 are divalent alkyl groups, while those in the definitions of R3 are monovalent alkyl groups. In the definitions of R2, R4, and R6, preferred alkyl groups are C1-C6 alkyl, and the most preferred are C2-C4 alkyl. The term xe2x80x9carylxe2x80x9d is used to denote the phenyl group and fused aromatic hydrocarbyl groups such as naphthyl, and phenanthryl. The preferred aryl group is phenyl. The term xe2x80x9csubstitutedxe2x80x9d is used to denote substituents that are inert to the reaction.
While R3 is defined as either a pendant arm or a portion of an additional cyclic structure with the adjacent atoms, preferred R3s are pendant arms, and preferred pendant arms are alkyl phosphonic acids, dialkyl esters of alkyl phosphonic acids, diaryl esters of alkyl phosphonic acids, and alkyl aryl esters of alkyl phosphonic acids. The xe2x80x9calkylxe2x80x9d in the term xe2x80x9calkyl phosphonic acidxe2x80x9d denotes a divalent alkyl group the links the phosphorus atom to the nitrogen atom. Preferred divalent alkyl groups within this definition are C1-C4 alkyl, more preferred are C1-C2 alkyl, and the most preferred is the methylene group. On the ester portion of the group, the preferred groups are alkyl groups, particularly C1-C6 alkyl, and the most preferred are C1-C3 alkyl.
The bridging agent is a reactant having two reactive sites that will undergo a nucleophilic attack by the two N-H groups on the starting polyamine to place the R6 bridge in the location shown in the formula of the cyclized product. Nucleophilic reactions are well known among those skilled in synthetic chemistry, and the groups that will serve effectively in the nucleophilic reactions at the two reactive sites on the bridging agent will be readily apparent to the skilled organic chemist. Examples of these groups are oxo, alkyl or aryl halides, and p-toluene sulfonate. The term xe2x80x9coxoxe2x80x9d denotes an oxygen atom joined to a carbon atom on the bridging agent through a double bond, and bridging agents that contain oxo groups as the electrophiles are either aldehydes or ketones. Following nucleophilic attack on an oxo group the intermediate formed is reduced to form the desired product. The term xe2x80x9chalidexe2x80x9d denotes a halogen atom, of which fluoride, chloride, bromide, or iodide, with chloride and bromide are the most preferred. When the leaving groups are oxo groups, the reaction is preferably conducted in the presence of reducing agents, preferably hydrogen and an hydrogenation catalyst, examples of which are nickel, cobalt, copper, chromium, platinum, and palladium. A preferred hydrogenation catalyst is nickel. The residue of the bridging agent is defined by the definition given above for R6.
The temperature at which the reaction is conducted can vary widely and is not critical to this invention. In general, the formation of undesired products and the degradation of the desired product can be minimized if the reaction temperature is maintained below 120xc2x0 C. In the preferred practice of the cyclization reaction of the invention, the operating temperature is maintained within the range of about 20xc2x0 C. to about 70xc2x0 C. Likewise, the concentration of the reactants can vary and is not critical, although one advantage of the invention is that the reaction can be performed at concentrations higher than the processes of the prior art for forming the same products. Accordingly, in the preferred practice of this aspect of the invention, the concentration of the starting compound (i.e., the polyamine to be cyclized) is at least about 0.03 M, and most preferably from about 0.05 M to about 2.0 M.
The reaction can be performed either neat (i.e., in the absence of a solvent or in the presence of very little solvent) or in the presence of a solvent in significant amounts. When a solvent is used, protic solvents are preferred, and the most preferred among these are alcohols such as a C1-C4 alkyl alcohol.
In the aspects of this invention that relate to the incorporation of a methylenephosphonate ester into a linear polyamine, the starting material is a compound of the formula 
in which R2, R4, and n are as defined above, a tri-substituted phosphite of the formula 
in which R11, R12, and R13 are either the same or different and are each either alkyl or aryl, and a source of formaldehyde, the reaction being conducted in the presence of water. The terms xe2x80x9calkylxe2x80x9d and xe2x80x9carylxe2x80x9d are used here in the same manner as set forth above. The product of the reaction is a compound having the formula 
in which R1, R3, and R5 are methylenephosphonate ester groups of the formula 
In preferred embodiments of this aspect of the invention, R2 and R4 are each C1-C6 alkyl and most preferably C2-C4 alkyl. Likewise, in preferred embodiments, R11, R12, and R13 are each C1-C6 alkyl, and most preferably C1-C3 alkyl. Preferred values for n are 1 and 2.
The source of formaldehyde that is included among the reactants is any substance that will release formaldehyde for reaction with the polyamine and the tri-substituted phosphite in the reaction medium. Aqueous formaldehyde and paraformaldehyde are common sources of formaldehyde. Other sources of formaldehyde will be readily apparent to the skilled organic chemist. When aqueous formaldehyde is used the water associated with the formaldehyde may be a sufficient source of water in the reaction. When paraformaldehyde is used water must be introduced into the reaction from another source.
The conditions under which this reaction is conducted may vary and are not critical to this aspect of the invention. In the preferred practice of the invention, the reaction is conducted within operating conditions within certain ranges. The weight ratio of water to formaldehyde, for example, is preferably at least about 3:2. Likewise, the temperature at which the reaction is performed is preferably a maximum of about 40xc2x0 C., and most preferably within the range of from about 10xc2x0 C. to about 40xc2x0 C. The reaction may also be conducted in the additional presence of a protic solvent other than water. Preferred such solvents are alcohols such as a C1-C4 alkyl alcohol.
Once the methylenephosphonate esters are bonded to the nitrogen atoms, the product can either be cyclized by action of the bridging agent in accordance with the reaction described above, and then may be subjected to hydrolysis reactions. Alternatively, the linear compound can be directly hydrolyzed to convert any number of the ester groups to acid form. Hydrolysis is performed by conventional techniques well known to the skilled organic chemist. Hydrolysis can be achieved by treatment with either acid or base. Hydrolysis in base typically results in hydrolysis of one of the ester groups on each phosphonate moiety, while hydrolysis in acid typically hydrolyzes both ester groups on each phosphonate moiety.
The hydrolysis reaction is illustrated on the non-cyclized polyamine as follows:
The starting material is a compound of the formula 
in which R2, R4, and n are as defined above. This compound is reacted with a tri-substituted phosphite of the formula 
in which R11, R12, and R13 are as defined above, and a source of formaldehyde in the presence of water. This reaction yields an intermediate of the formula 
in which R1, R3, and R5 are methylenephosphonate radicals of the formula 
This intermediate is then hydrolyzed to convert R11 to H. Preferably, any R12 that is other than H is also converted to H.
New compositions of matter within the scope of this invention are the compounds having the formula 
in which R21 and R22 are either the same or different, and are either H, alkyl, or aryl. The terms xe2x80x9calkylxe2x80x9d and xe2x80x9carylxe2x80x9d are as defined above. A preferred class of compounds are those in which R21 and R22 are either H or C1-C6 alkyl, and a further preferred class are those in which R21 and R22 are either H or C1-C6 alkyl. A still further preferred class are those in which these groups are either H or ethyl. Specific examples are N,Nxe2x80x2,Nxe2x80x3-tris(methylene-phosphonate diethyl ester)-1,4,7-triazaheptane (the above formula in which R21 and R22 are each ethyl), N,Nxe2x80x2,Nxe2x80x3-tris(methylenephosphonate ethyl ester)-1,4,7-triazaheptane (the above formula in which R21 is H, and R22 is ethyl), and N,Nxe2x80x2,Nxe2x80x3-tris(methylenephosphonic acid)-1,4,7-triazaheptane (the above formula in which R21 and R22 are each H). These compounds and all others within the scope of the generic formula shown above are synthesized by the methods disclosed in this specification, and are useful for each of the uses set forth above in the xe2x80x9cDescription of the Prior Artxe2x80x9d section of this specification.
The following examples are offered strictly for purposes of illustration.